WO2013109632A2 - Composés organiques - Google Patents

Composés organiques Download PDF

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Publication number
WO2013109632A2
WO2013109632A2 PCT/US2013/021749 US2013021749W WO2013109632A2 WO 2013109632 A2 WO2013109632 A2 WO 2013109632A2 US 2013021749 W US2013021749 W US 2013021749W WO 2013109632 A2 WO2013109632 A2 WO 2013109632A2
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WIPO (PCT)
Prior art keywords
compound
formula
salt form
free
pharmaceutically acceptable
Prior art date
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PCT/US2013/021749
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English (en)
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WO2013109632A3 (fr
Inventor
Barry S. Coller
Craig Thomas
Marta Filizola
Joshua Mccoy
Wenwei Huang
Min Shen
Jian-kang JIANG
Original Assignee
The Rockefeller University
National Institutes Of Health
Mount Sinai School Of Medicine
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Publication date
Application filed by The Rockefeller University, National Institutes Of Health, Mount Sinai School Of Medicine filed Critical The Rockefeller University
Priority to US14/372,488 priority Critical patent/US9303044B2/en
Priority to DK13738252.9T priority patent/DK2804610T3/en
Priority to ES13738252T priority patent/ES2708201T3/es
Priority to CN201380010564.7A priority patent/CN104936598B/zh
Priority to CA2861350A priority patent/CA2861350C/fr
Priority to EP13738252.9A priority patent/EP2804610B1/fr
Priority to IN6580DEN2014 priority patent/IN2014DN06580A/en
Priority to AU2013209884A priority patent/AU2013209884C1/en
Publication of WO2013109632A2 publication Critical patent/WO2013109632A2/fr
Publication of WO2013109632A3 publication Critical patent/WO2013109632A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/436—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having oxygen as a ring hetero atom, e.g. rapamycin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/726—Glycosaminoglycans, i.e. mucopolysaccharides
    • A61K31/727—Heparin; Heparan
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/02—Inorganic materials
    • A61L31/022—Metals or alloys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/08—Materials for coatings
    • A61L31/10—Macromolecular materials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L31/16—Biologically active materials, e.g. therapeutic substances
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/416—Anti-neoplastic or anti-proliferative or anti-restenosis or anti-angiogenic agents, e.g. paclitaxel, sirolimus
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/42—Anti-thrombotic agents, anticoagulants, anti-platelet agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/45—Mixtures of two or more drugs, e.g. synergistic mixtures

Definitions

  • the present invention relates to compounds and compositions useful for inhibiting or reducing platelet deposition, adhesion and/or aggregation.
  • the present invention further relates to drug-eluting stent and methods of treatment or prophylaxis of thrombotic disorders, including stroke, myocardial infarction, unstable angina, abrupt closure following angioplasty or stent placement, thrombosis induced by peripheral vascular surgery, peripheral vascular disease or thrombotic disorders resulting from atrial fibrillation or inflammation.
  • Platelet accumulation at sites of vascular injury is a dynamic process that mediates formation of both the primary hemostatic plug and pathologic thrombus formation.
  • the mechanisms by which platelet surface proteins direct platelet recruitment to thrombi under flow conditions have been studied in detail.
  • cell- surface receptor interactions activate intracellular signaling. Intracellular signaling stimulates the release of thrombogenic substances from platelet granules. Signaling also mediates activation of the platelet integrin ⁇ 3 ⁇ 4 ⁇ 3 that facilitates firm adhesion of the platelets at the sites of injury.
  • Platelets form the body's primary means of hemostasis and, as such, have developed an elaborate mechanism of surveying the vasculature for defects in endothelial integrity. This mechanism involves the ability to respond to
  • the platelet has only a small repertoire of major functional outputs. Upon activation, platelets change shape, aggregate, and secrete their granular contents.
  • the process of platelet activation involves the expression of activities not shared by functionally intact resting platelets, including, for example, ATP release, serotonin release, lysosomal release, alpha granule release, dense granule release, and cell surface expression of markers of activated platelets [including, but not limited to P-selectin and activated ⁇ 3 ⁇ 4 ⁇ 3 (GPIIb/IIIa) receptor].
  • platelet activation results in the aggregation of platelets with each other and attachment to non-platelet surrounding cells.
  • the granular contents of platelets supply additional adhesion molecules, growth factors, coagulation enzymes and other specialized molecules instrumental in the process of thrombus formation and the initiation of the healing process.
  • Inhibitors of platelet activity can provide therapeutic and preventive benefits for each of these diseases or disorders. It is also possible that inappropriate platelet activation plays a role in venous thrombosis, such that platelet inhibitors can be useful for the treatment or prophylaxis of disorders associated with such thromboses.
  • aspirin is a relatively weak platelet inhibitor.
  • aspirin can cause life-threatening allergic reactions in sensitive individuals.
  • ticlopidine Teclid.TM., Roche Pharmaceuticals
  • ticlopidine Teclid.TM., Roche Pharmaceuticals
  • the drug can also cause thrombotic thrombocytopenic purpura as well as life threatening leukopenia, nausea, abdominal pain, dyspepsia, diarrhea and skin rash.
  • clopidogrel is another platelet inhibitor that requires the generation of active metabolites for its therapeutic efficacy. Therefore, clopidogrel also has a delay of at least several hours for its effect. Clopidogrel can also cause thrombotic
  • thrombocytopenia purpura The drug has also been associated with a number of side effects, including rash, edema, hypertension, hypercholesterolemia, nausea, abdominal pain, dyspepsia, diarrhea, urinary tract infections, liver enzyme elevations and arthralgia.
  • the platelet inhibitory agent abciximab (c7E3 Fab, Reopro ® , manufacturer-Centocor B. V., distributor- Eli Lilly and Co.) is only available in a parenteral form.
  • the drug can cause severe thrombocytopenia. Its antiplatelet effects last for several days unless platelet transfusions are given and, therefore, may complicate surgery that is sometimes required in the setting of life-threatening arterial occlusion (e.g., emergent cardiac surgery in the setting of a myocardial infarction).
  • integrin ⁇ 3 ⁇ 4 ⁇ 3 is a receptor on the surface of human platelets.
  • the dimer is responsible for binding adhesive plasma proteins, most notably fibrinogen and von Willebrand factor (vWF).
  • fibrinogen and von Willebrand factor (vWF).
  • vWF von Willebrand factor
  • the binding of fibrinogen, vWF and other ligands by ⁇ 3 ⁇ 4 ⁇ 3 is mediated principally though the peptide recognition sequence Arg-Gly- Asp (RGD) or the fibrinogen ⁇ chain dodecapeptide HHLGGAKQAGDV.
  • Conformational changes in ⁇ 3 ⁇ 4 ⁇ 3 are thought to occur upon the binding of ligand to the receptor, leading to the exposure of ligand- induced binding sites (LIBS) as detected by LIBS-specific monoclonal antibodies (mAbs). Electron microscopy and crystal structures of the integrin in complex with various R(K)GD-like ligands support the theory that the integrin undergoes a major conformational change after or during ligand binding.
  • LIBS ligand- induced binding sites
  • peptidomimetic tirofiban
  • Both inhibitors act by competitively blocking the binding site for fibrinogen.
  • tirofiban Aggrastat.TM., Merck and Co., Inc.
  • Eptifibatide Integrilin.TM., COR Therapeutics, Inc., Key Pharmaceuticals Inc. is also only available for parenteral administration and it too can cause
  • Crystal structure studies of the ⁇ 3 ⁇ 4 ⁇ 3 headpiece demonstrates that these inhibitors bind to both allb and to the divalent cation in the ⁇ 3 subunit's metal ion dependant adhesion site (MIDAS). It is believed that the interaction with the MIDAS metal ion induces conformational changes in the ⁇ 3 which leads to the increased the risk for thrombotic complications following ⁇ 3 ⁇ 4 ⁇ 3 inhibitor therapy.
  • MIDAS metal ion dependant adhesion site
  • the present invention thus provides ⁇ 3 ⁇ 4 ⁇ 3 antagonists, pharmaceutical compositions, drug-eluting stent comprising ⁇ 3 ⁇ 4 ⁇ 3 antagonists and new methods of treatment and prophylaxis using ⁇ 3 ⁇ 4 ⁇ 3 antagonists.
  • A is carbon or nitrogen
  • B is carbon or nitrogen, provided that when B is nitrogen, R 3 does not exist;
  • P2 is H or halo (e.g., fluoro);
  • R a , R a ' , R b , R b ' ,R C , R d , R d ' , R e ,and R e ' are H;
  • halo e.g., bromo
  • haloCi_ 4 alkyl e.g., CF 3
  • hydroxy-Ci_ 4 alkyl -C
  • the compound of Formula P is a compound of Formula I:
  • R 2 is H
  • R a , R a ' , R b , R b ' ,R C , R d , R d ' , R e ,and R e ' are H;
  • halo e.g., bromo
  • haloCi_ 4 alkyl e.g., CF 3
  • hydroxy-Ci_ 4 alkyl -C(H)(OH)CH
  • the invention provides the compound of Formula P and Formula I as follows:
  • halo e.g., bromo
  • halo e.g., bromo
  • haloCi ⁇ alkyl e.g., CF 3
  • hydroxy-Ci ⁇ alkyl - C(H)(OH)CH 3
  • acetyl
  • R 2 is H or halo (e.g., fluoro);
  • R a , R a ' , R b , R b ' ,R C , R d , R d ' , R e ,and R e ' are H;
  • haloCi_ 4 alkyl e.g., CF 3
  • hydroxy- Ci_ 4 alkyl -C(H)(OH)CH 3 or -CH 2 (OH)
  • A is carbon
  • R 2 is H or halo (e.g., fluoro);
  • R a , R a ' , R b , Rb' ,Rc, Rd, Rd' , R e ,and R e ' are H;
  • haloCi ⁇ alkyl e.g., CF 3
  • hydroxy- Ci_ 4 alkyl - C(H)(OH)CH 3 or -CH 2 (OH)
  • the invention provides a compound of Formula P-II:
  • A is carbon or nitrogen
  • R 2 is H or halo (e.g., fluoro);
  • the compound of Formula P-II is a compound of Formula II:
  • the invention provides the compound according to Formula P-II or Formula II, wherein said compound has an IC 50 value of less than 100 ⁇ , in an aggregation assay as described in Example 15 and/or a percentage of inhibition of greater than 30%, at a concentration of ⁇ or less in an adhesion assay as described in Example 15, in free or salt form.
  • the invention provides a Pharmaceutical Composition comprising the Compound of Formula P, or any of 1.1-1.43, in free or pharmaceutically acceptable salt form, in combination or association with a pharmaceutically acceptable diluent or carrier (Pharmaceutical Composition P).
  • the invention provides a Pharmaceutical Composition comprising the Compound of Formula I, or any of 1.1-1.27, 1.41-1.43, in free or pharmaceutically acceptable salt form, in combination or association with a pharmaceutically acceptable diluent or carrier (Pharmaceutical Composition I).
  • the invention provides a Pharmaceutical Composition comprising the Compound of Formula I, or any of 1.1-1.27, 1.41-1.43, in free or pharmaceutically acceptable salt form, in combination or association with a pharmaceutically acceptable diluent or carrier (Pharmaceutical Composition I).
  • the invention provides a Pharmaceutical Composition comprising the Compound of Formula I, or any of 1.1-1.27, 1.41-1.43, in free or pharmaceutically acceptable salt form, in combination or association with a pharmaceutically
  • compositions comprising the Compound of Formula P-II, in free or pharmaceutically acceptable salt form, in combination or association with a pharmaceutically acceptable diluent or carrier (Pharmaceutical Composition P-II).
  • the Pharmaceutical Composition P-II comprises the compound of Formula II, in free or pharmaceutically acceptable salt form (Pharmaceutical Composition II).
  • the Pharmaceutical Compositions of the Invention as hereinbefore described are useful, e.g., for preventing or inhibiting platelet adhesion and/or aggregation in treating thrombotic a disorder in a subject in need thereof.
  • the invention provides the Pharmaceutical Compositions of the Invention as hereinbefore described useful for inhibiting or reducing platelet aggregation and/or adhesion.
  • the invention provides a method for inhibiting or reducing platelet aggregation and/or adhesion comprising administering to a subject in need thereof, an effective amount of the Compound of Formula P, any of 1.1-1.43, in free or pharmaceutically acceptable salt form, such that platelet aggregation and/or adhesion is reduced (Method P).
  • the invention provides a method for inhibiting or reducing platelet aggregation and/or adhesion comprising administering to a subject in need thereof, an effective amount of the Compound of Formula I, or any of 1.1-1.27, 1.41-1.43, in free or pharmaceutically acceptable salt form, such that platelet aggregation and/or adhesion is reduced (Method I).
  • the invention provides a method for inhibiting or reducing platelet aggregation and/or adhesion comprising administering to a subject in need thereof, an effective amount of a Compound of Formula P-II, in free or pharmaceutically acceptable salt form, such that platelet aggregation and/or adhesion is reduced (Method P-II).
  • Method P-II comprises administering to a subject in need thereof, an effective amount of a Compound of Formula II (Method II), in free or
  • the invention provides Method P, I, P-II or II, wherein reduction of platelet aggregation and/or adhesion treats or prevent a thrombotic disorder, e.g. selected from a group consisting of stroke, myocardial infarction, unstable angina, abrupt closure following angioplasty or stent placement, thrombosis induced by peripheral vascular surgery, peripheral vascular disease or thrombotic disorders resulting from atrial fibrillation or inflammation.
  • a thrombotic disorder e.g. selected from a group consisting of stroke, myocardial infarction, unstable angina, abrupt closure following angioplasty or stent placement, thrombosis induced by peripheral vascular surgery, peripheral vascular disease or thrombotic disorders resulting from atrial fibrillation or inflammation.
  • the invention provides a method for the treatment or prophylaxis of a thrombotic disorder comprising administering to a subject at risk of a thrombotic disorder, an effective amount of the Compound of Formula P, or any of 1.1-1.43, in free or pharmaceutically acceptable salt form, such that platelet aggregation and/or adhesion is reduced (Method P-III).
  • the invention provides a method for the treatment or prophylaxis of a thrombotic disorder comprising administering to a subject at risk of a thrombotic disorder, an effective amount of the Compound of Formula I, or any of 1.1-1.27, 1.41-1.43, in free or pharmaceutically acceptable salt form, such that platelet aggregation and/or adhesion is reduced (Method III).
  • the invention provides a method for the treatment or prophylaxis of a thrombotic disorder comprising administering to a subject at risk of a thrombotic disorder, an effective amount of the Compound of Formula P-II, in free or pharmaceutically acceptable salt form, such that platelet aggregation and/or adhesion is reduced (Method P-IV).
  • Method P-IV comprises administering to a subject at risk of a thrombotic disorder, an effective amount of the Compound of Formula P-II, in free or pharmaceutically acceptable salt form (Method IV).
  • the invention further provides for the following methods: Method P-III, III, P-IV or IV, wherein said thrombotic disorder is selected from a group consisting of stroke, myocardial infarction, unstable angina, abrupt closure following angioplasty or stent placement, thrombosis induced by peripheral vascular surgery, peripheral vascular disease or thrombotic disorders resulting from atrial fibrillation or inflammation;
  • Method P-III, III, P-IV or IV wherein said thrombotic disorder is thrombosis as a result of angioplasty or stent placement;
  • Method P-III, III, P-IV or IV wherein subject at risk of thrombotic disorder is a subject who has a history of vascular surgery;
  • Method P-III , III, P-IV or IV, or any of Methods 7.1-7.3 further comprises administering to said subject an effective amount of at least one therapeutic agent selected from a group consisting of anticoagulant, antiplatelet, and thrombolytic agents in conjunction with the Compound P, I, P-II or II of the current invention as hereinbefore described, in free or pharmaceutically acceptable salt form;
  • Method P-III, III, P-IV or IV or any of Methods 7.1-7.4, further comprises administering to said subject an effective amount of at least one therapeutic agent selected from a group consisting of heparin, low molecular weight heparins, bivalirudin, Fondaparinux, warfarin,
  • the invention further provides any of the foregoing methods wherein the compounds of the present invention (a) reduce platelet inhibition with a percentage of inhibition of greater than 30%, preferably greater than 50% at a concentration of 100 ⁇ or less; and/or (b) reduce platelet aggregation, e.g., with an IC 50 of less than 100 ⁇ , preferably less than 25 ⁇ in an ADP or other agonist- induced platelet aggregation assay and/or in a fibrinogen binding assay as described in the examples below.
  • the compounds of the present invention (a) reduce platelet inhibition with a percentage of inhibition of greater than 30%, preferably greater than 50% at a concentration of 100 ⁇ or less; and/or (b) reduce platelet aggregation, e.g., with an IC 50 of less than 100 ⁇ , preferably less than 25 ⁇ in an ADP or other agonist- induced platelet aggregation assay and/or in a fibrinogen binding assay as described in the examples below.
  • the invention is a method for the treatment or prophylaxis of a thrombotic disorder comprising administering heparin in conjunction with the Compound of Formual P, I, P-II or II of the current invention as hereinbefore described, in free or pharmaceutically acceptable salt form, particularly the Compound of Formula P of Formual I, in free or pharmaceutically acceptable salt form.
  • the present invention identifies ⁇ 3 ⁇ 4 ⁇ 3 inhibitors that are capable of inhibiting fibrinogen binding without inducing the binding of one more integrin ⁇ 3 LIBS-specific mAbs.
  • the Compounds of the Invention e.g., the Compound of Formula P, I, P- II or II in free or salt form may bind to ocllb, and in some cases induce ocllb LIBS exposure, without inducing ⁇ 3 LIBS exposure.
  • Such compounds thus demonstrate specific binding to ⁇ 3 ⁇ 4 ⁇ 3 integrin and inhibition of platelet adhesion without the disadvantage of inducing the change in conformation of the ⁇ 3 and consequent risk of complications following dissociation of the compounds from the ⁇ 3 ⁇ 4 ⁇ 3.
  • the invention provides a drug-eluting stent wherein the drug or drugs eluted comprise the Compound of Formula P, or any of 1.1-1.43, in free or pharmaceutically acceptable salt form as hereinbefore described.
  • the invention provides a drug-eluting stent wherein the drug or drugs eluted comprise the Compound of Formula I, or any of 1.1-1.27,
  • the invention provides a drug-eluting stent wherein the drug or drugs eluted comprise the compound of Formula P-II or Formula
  • the invention provides a stent, e.g., an arterial stent, for example a coronary artery or carotid artery stent, which comprises a biocompatible polymer matrix which comprises or is associated with the Compound of Formula P, I, P-II or II, in free or pharmaceutically acceptable salt form as hereinbefore described.
  • the stent may be made of metal, plastic, biodegradable or bioabsorbable material or combination thereof, e.g., stainless steel, nickel-titanium alloy, colbalt-alloy, tantalum, silicone, polytetrafluoroethylene, magnesium alloy or poly-L-lactide.
  • a stent may be a metallic stent (e.g., stainless steel, nickel-titanium alloy, colbalt alloy, or tantalum) partially or wholly coated with a biocompatible polymer, e.g., a plastic (e.g., polytetrafluoroethylene) or a polymeric carrier (e.g., phosphorylcholine or polylactic acid) which polymer comprises or is associated with the Compound P, I, P- II or II, in free or pharmaceutically acceptable salt form as hereinbefore described, e.g., such that said Compound is presented or released in a manner and amount effective to inhibit platelet adhesion and/or aggregation in the vicinity of the stent.
  • a biocompatible polymer e.g., a plastic (e.g., polytetrafluoroethylene) or a polymeric carrier (e.g., phosphorylcholine or polylactic acid) which polymer comprises or is associated with the Compound P, I, P- II or II,
  • the stent may further comprise or be associated with an additional drug or drugs, e.g., an antiproliferative agent, e.g., sirolimus, everolimus, zotarolimus, tacrolimus, or paclitaxel, and/or an anticoagulant, e.g., heparin.
  • an antiproliferative agent e.g., sirolimus, everolimus, zotarolimus, tacrolimus, or paclitaxel
  • an anticoagulant e.g., heparin.
  • the invention provides the Compound of Formula P, or any of 1.1-1.43, in free or pharmaceutically acceptable salt form as hereinbefore described, for use as a pharmaceutical, e.g. use of the Compound of Formula P, or any of 1.1-1.43, in free or pharmaceutically acceptable salt form as hereinbefore described, e.g., (in the manufacture of a medicament) for the treatment or prophylaxis of a thrombotic disorder, e.g., according to any of Methods P, P-III or any of methods 7.1-7.7.
  • the invention provides the Compound of Formula I, or any of 1.1-1.27, 1.41-1.43, in free or pharmaceutically acceptable salt form as hereinbefore described, for use as a pharmaceutical, e.g. use of the Compound of Formula I, or any of 1.1-1.27, 1.41-1.43, in free or pharmaceutically acceptable salt form as hereinbefore described, e.g., (in the manufacture of a medicament) for the treatment or prophylaxis of a thrombotic disorder, e.g., according to any of Methods I, III or any of methods 7.1-7.7.
  • the invention provides the Compound of Formula P-II or Formula II, in free or pharmaceutically acceptable salt form, e.g., (in the manufacture of a medicament) for the treatment or prophylaxis of a thrombotic disorder, e.g., according to any of methods P-II, II, P-IV, IV or any of methods 7.1-7.7.
  • the invention provides a Pharmaceutical Composition comprising the Compound of Formula P, or any of 1.1-1.43, in free or pharmaceutically acceptable salt form as hereinbefore described, for use as a pharmaceutical e.g., (in the manufacture of a medicament) for the treatment or prophylaxis of a thrombotic disorder, e.g., according to any of Methods P, P-III, or any of methods 7.1-7.7.
  • the invention provides a Pharmaceutical Composition comprising the Compound of Formula I, or any of 1.1-1.27, 1.41-1.43, in free or pharmaceutically acceptable salt form as hereinbefore described, for use as a pharmaceutical e.g., (in the manufacture of a medicament) for the treatment or prophylaxis of a thrombotic disorder, e.g., according to any of Methods I, III or any of methods 7.1-7.7.
  • the invention provides a Pharmaceutical Composition comprising the Compound of Formula P-II or Formula II, in free or pharmaceutically acceptable salt form as hereinbefore described, for use as a pharmaceutical e.g., (in the manufacture of a medicament) for the treatment or prophylaxis of a thrombotic disorder, e.g., according to any of Methods P-II, II, P-IV, IV or any of methods 7.1-7.7.
  • ⁇ 3 ⁇ 4 ⁇ 3 or "integrin ⁇ 3 ⁇ 4 ⁇ 3” refers to the receptor on the surface of human platelets. It is a heterodimeric complex composed of both ocllb and ⁇ 3 subunits responsible for binding adhesive plasma proteins, most notably fibrinogen and von Willebrand factor.
  • antagonist refers to any ligand or molecule that binds to receptors and competitively or noncompetitively blocks the binding of ligand to that receptor. Therefore, " ⁇ 3 ⁇ 4 ⁇ 3 antagonist” refers to any ligand or molecule that competitively or noncompetitively blocks ⁇ 3 ⁇ 4 ⁇ 3.
  • LIBS refers to ligand-induced binding sites on ⁇ 3 ⁇ 4 ⁇ 3 that are presented or exposed upon the binding of a ligand or antagonist by the receptor.
  • LIBS -specific mAbs refers to monoclonal antibodies that bind to the exposed ligand-induced binding sites of ⁇ 3 ⁇ 4 ⁇ 3. Examples of LIBS-specific mAbs include AP5, PMI-1 and LIBS1.
  • thrombotic disorders refers to disorders characterized by formation of a thrombus that obstructs vascular blood flow.
  • thrombotic disorders include stroke, myocardial infarction, stable or unstable angina, peripheral vascular disease, abrupt closure following angioplasty or stent placement and thrombosis induced by vascular surgery.
  • thrombootic disorders also include disorders characterized by formation of a thrombus caused by atrial fibrillation or inflammation.
  • subject at risk of thrombotic disorders or “subject in need thereof includes subjects who have a history of vascular intervention (e.g.
  • cardiovascular abnormality e.g. atrial fibrillation
  • CAD coronary artery disease
  • systemic hypertension diabetes mellitus, hyperlipidemia, bicuspid aortic valve, hypertrophic cardiomyopathy or mitral valve prolapse.
  • subject may include human or non-human (e.g., an animal).
  • platelet adhesion refers to the binding of platelet membrane proteins to fibrinogen, collagen, von Willebrand factor (vWF) or other adhesive glycoproteins (e.g., fibronectin, laminin).
  • vWF von Willebrand factor
  • platelet aggregation refers to the attachment of activated platelets one to another, which results in the formation of aggregates or clumps of activated platelets.
  • inhibitor or reduce platelet adhesion and/or aggregation is intended to mean at least a 30% inhibition of platelet activity at a concentration of 100 ⁇ or lower in a given assay, relative to platelet activity in the absence of the compound.
  • antagonist known to expose ⁇ 3 LIBS herein refers to agents that induce conformational in ⁇ 3, for example tirofiban.
  • anticoagulants refers to any compound or substance that either stimulates natural inhibitor of coagulant proteases or blocks the coagulation cascade.
  • anticoagulants include, but are not limited to heparin, warfarin, phenprocoumon, fondaparinux, lepirudin, bivalirudin, argatroban, danaparoid and drotrecogin alfa.
  • anti-platelet agents refers to compound or substance that prevents platelet adhesion and/or aggregation.
  • anti-platelet agents include, but are not limited to prasugrel, aspirin, ticlopidine, clopidogrel, ticagrelor, abciximab, eptifibatide and tirofiban.
  • fibrinolytic agents therefore refers to any compound or substance that lyses pathological thrombi.
  • Thrombolytic agents are agents that are fibrinolytic, i.e., agents that convert plasminogen to plasmin, which lyses fibrin.
  • fibrinolytic agents include but are not limited to streptokinase and tissue plasminogen activator (t-PA).
  • stent refers to expandable wire form or perforated tube that is inserted into a natural conduit of the body, such as an artery, usually a coronary artery, to prevent or counteract a disease-induced localized flow
  • phenyl optionally substituted with one or more nitro means in some instances, the phenyl is substituted with one or more nitro groups and in other instances, the phenyl is unsubstituted.
  • the binding of LIBS-specific mAbs to ⁇ 3 ⁇ 4 ⁇ 3 may be measured by comparing the binding of LIBS-specific mAbs to ⁇ 3 ⁇ 4 ⁇ 3 in the presence of testing compound with the binding of LIBS-specific mAbs to ocllb ⁇ 3 in the absence or presence of a control such as untreated platelets and/or other known ⁇ 3 ⁇ 4 ⁇ 3 inhibitors that are known to cause ⁇ 3 LIBS exposure, e.g., tirofiban.
  • the test compound may bind to ocllb and optionally increases binding of at least one ocllb
  • LIBS-specific mAb relative to binding to unactivated platelets without increasing the binding of one or more ⁇ 3 LIBS-specific mAbs relative to binding to unactivated platelets and/or produces less binding relative to binding in the presence of an agent known to bind to and directly activate ⁇ 3 ⁇ 4 ⁇ 3 so as to expose ⁇ 3 LIBS.
  • alkyl or “alkyl chain” or “alkylene” refers to a linear or branched, saturated or unsaturated, aliphatic hydrocarbon. Unless otherwise specified, alkyl refers to a hydrocarbon chain containing one to four carbon atoms. Examples of alkyl may include, but are not limited to methyl, ethyl, tert-butyl and the like as well as alkenyl or alkynyl substituents.
  • C 3 -Ci 0 cycloalky or “C 3 -i 0 cycloalky” refers to fully or partially saturated, carbocyclic, non-aromatic hydrocarbon radicals having three to eight carbon atoms.
  • Examples of C3-Ciocycloalkyl optionally containing one or more heteroatoms selected from a group consisting of O or N include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl or cyclohexenyl, piperidinyl, piperazinyl, morpholinyl, imidazolinyl, pyrrolidinyl.
  • C 3 - Ciocycloalky may also refer to non-aromatic cyclic system fused to an aromatic cyclic system. An example of this includes tetrahydroquinolinyl.
  • aryl refers to any aromatic ring system. Aromatic compounds include phenyl, naphthyl and their derivatives.
  • heteroaryl is intended to mean a stable 5- to 6-membered monocyclic or 7- to 14-membered bicyclic heterocyclic ring which is saturated partially unsaturated or unsaturated (aromatic), and which consists of carbon atoms and 1 , 2, 3 or 4 heteroatoms independently selected from the group consisting of N, O and S and including any bicyclic group in which any of the above-defined
  • heterocyclic rings is fused to another ring.
  • acyl is intended to encompass R-C(O)- wherein R is Ci_ 4 alkyl, wherein said alkyl is optionally substituted with one or more halo, hydroxy, or Ci_ 4 alkoxy.
  • R is Ci_ 4 alkyl
  • acyl is CH 3 -C(0)-.
  • the Compounds of the Invention may comprise one or more chiral carbon atoms.
  • the compounds thus exist in individual isomeric, e.g., enantiomeric or diasteriomeric form or as mixtures of individual forms, e.g., racemic/diastereomeric mixtures. Any isomer may be present in which the asymmetric center is in the (R)-, (S)-, or (R,S)- configuration.
  • the invention is to be understood as embracing both individual optically active isomers as well as mixtures (e.g., racemic/diasteromeric mixtures) thereof.
  • the Compound of the Invention may be a racemic mixture or it may be predominantly, e.g., in pure, or substantially pure, isomeric form, e.g., greater than 70% enantiomeric excess ("ee"), preferably greater than 80% ee, more preferably greater than 90% ee, most preferably greater than 95% ee.
  • ee enantiomeric excess
  • the purification of said isomers and the separation of said isomeric mixtures may be accomplished by standard techniques known in the art (e.g., column chromatography, preparative TLC, preparative HPLC, simulated moving bed and the like)
  • Compounds of the Invention may exist in free or salt form, e.g., as acid addition salts (e.g., hydrochloric acid, toluene sulfonic acid, methane sulfonic acid, benzene sulfonic acid, trifluoroacetic acid, and the like).
  • acid addition salts e.g., hydrochloric acid, toluene sulfonic acid, methane sulfonic acid, benzene sulfonic acid, trifluoroacetic acid, and the like.
  • acid addition salts e.g., hydrochloric acid, toluene sulfonic acid, methane sulfonic acid, benzene sulfonic acid, trifluoroacetic acid, and the like.
  • Salts which are unsuitable for pharmaceutical uses may be useful, for example, for the isolation or purification of free Compounds of the Invention or their pharmaceutically acceptable salts, are therefore also included.
  • the salt of the compound of the invention is a trifluoroacetic acid addition salt.
  • Compounds of the Invention may in some cases also exist in prodrug form.
  • a prodrug form is compound which converts in the body to a Compound of the Invention.
  • these substituents may form physiologically hydrolysable and acceptable esters.
  • physiologically hydrolysable and acceptable ester means esters of Compounds of the Invention which are hydrolysable under physiological conditions to yield acids (in the case of Compounds of the Invention which have hydroxy substituents) or alcohols (in the case of Compounds of the Invention which have carboxy substituents) which are themselves physiologically tolerable at doses to be administered.
  • the prodrug e.g., Drug-O-C(O)- CH 3
  • the prodrug may hydrolyze under physiological conditions to yield hydroxy (Drug-OH) on the one hand and acid, e.g., carboxylic acid on the other (e.g., CH 3 COOH), which are themselves physiologically tolerable at doses to be administered.
  • carboxylic acid group e.g., Drug- C(O)OH
  • its prodrug e.g., Drug-C(0)-0-CH 2 CH 3
  • the prodrug e.g., Drug-C(0)-0-CH 2 CH 3
  • Compounds of the present invention may be administered orally or parenterally, including intravenous, intramuscular, intraperitoneal, subcutaneous, transdermal, airway (aerosol), rectal, vaginal and topical (including buccal and sublingual) administration.
  • the compounds useful in the invention may generally be provided in the form of tablets or capsules, as a powder or granules, or as an aqueous solution or suspension. Tablets for oral use may include the active ingredients mixed with pharmaceutically acceptable excipients such as inert diluents, disintegrating agents, binding agents, lubricating agents, sweetening agents, flavouring agents, colouring agents and preservatives.
  • Suitable inert diluents include sodium and calcium carbonate, sodium and calcium phosphate, and lactose, while corn starch and alginic acid are suitable disintegrating agents. Binding agents may include starch and gelatin, while the lubricating agent, if present, will generally be magnesium stearate, stearic acid or talc. If desired, the tablets may be coated with a material such as glyceryl monostearate or glyceryl distearate, to delay absorption in the gastrointestinal tract.
  • Dosages of the compounds of the invention will vary depending upon the condition to be treated or prevented and on the identity of the inhibitor being used. Estimates of effective dosages and in vivo half-lives for the individual compounds encompassed by the invention can be made on the basis of in vivo testing using an animal model, such as the mouse model described herein or an adaptation of such method to larger mammals. Appropriate dosage may range from O.Olmg to 5000 mg. For example, one appropriate dosage may be 0.01-30mg/Kg, e.g., 26.5mg/Kg, e.g., 12mg/Kg.
  • the compounds useful according to the invention can be administered in combination or in conjunction with other known therapeutic agents useful for thrombotic disorders such as anticoagulants (e.g., heparin, warfarin, phenprocoumon, fondaparinux, lepirudin, bivalirudin, argatroban, danaparoid, drotrecogin alfa), fibrinolytic agents (e.g., streptokinase or tissue plasminogen activator (t-PA) or other anti -platelet agents (e.g., prasugrel, aspirin, ticlopidine, clopidogrel, ticagrelor, abciximab, eptifibatide and tirofiban).
  • anticoagulants e.g., heparin, warfarin, phenprocoumon, fondaparinux, lepirudin, bivalirudin, argatroban, danaparoid, drotrecogin alfa
  • fibrinolytic agents
  • Boc-Gly-OH N-(ieri-Butoxycarbonyl)glycine
  • Boc-Gly-NH 2 tert-butyl (2-amino-2-oxoethyl)carbamate
  • DIPEA diisopropylethylamine
  • EDC l-ethyl-3-(3-dimethylaminopropyl) carbodiimide
  • HATU (2-(7-Aza-lH-benzotriazole-l-yl)-l,l,3,3-tetramethyluronium, hexafluorophosphate ,
  • HC1 hydrochloric acid
  • Hunig's base ⁇ , ⁇ -diisopropylethylamine
  • MgS0 4 magnesium sulfate
  • aHC0 3 sodium bicarbonate
  • Na 2 S0 4 sodium sulfate
  • Na 2 S 2 0 4 sodium dithionite
  • NMO N-Methylmorpholine-N-oxide
  • Os0 4 osmium tetraoxide
  • PPA Polyphosphoric acid
  • POCI 3 phosphorous oxychloride
  • TFA trifluoroacetic acid
  • Xantphos 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene.
  • H NMR spectra are recorded on Varian 400 MHz spectrometers. Chemical Shifts are reported in ppm with DMSO-i3 ⁇ 4 as reference (2.50 ppm). All the analogues analyzed by NMR are TFA salt. Samples are analyzed for purity on an Agilent 1200 series LC/MS equipped with a Luna C18 (3 micron, 3x75 mm) reverse phase column having a flow rate of 0.8 mL/min. The mobile phase is a mixture of acetonitrile containing 0.025% trifluoroacetic acid (TFA) and H 2 0 containing 0.05% trifluoroacetic acid, respectively.
  • TFA trifluoroacetic acid
  • Example 1 The compound of Example 1 is prepared as described as described or similarly described in the procedures below:
  • Step 2 To a solution of 5-(3-bromo-5-nitrophenyl)-l,3,4-thiadiazol-2- amine (0.550 g, 1.827 mmol) in CH 3 CN (15 ml) is added methyl 3-chloro-3- oxopropanoate (0.235 ml, 2.192 mmol). The mixture is microwaved at 100 °C for 12 min. After cooling to room temperature, POCI 3 (5.96 ml, 63.9 mmol) and 'T ⁇ NEt
  • Step 3 To a mixture of 2-(3-bromo-5-nitrophenyl)-7-chloro-5H- [l,3,4]thiadiazolo[3,2-a]pyridin-5-one (312 mg, 0.81 mmol) and ieri-butyl piperazine- 1-carboxylate (180 mg, 0.968 mmol) in CH 3 CN (6 ml) is added i_ Pr 2 NEt (0.21 ml, 1.21 mmol) and the mixture is microwaved at 100 °C for 2 h. After cooling to room temperature, solid starts to precipitate out. The solid is filtered and washed with EtOAc and collected. The filtrate is concentrated in vacuo and the crude residue is purified by Biotage column chromatography (MeOH/DCM: 1/100 to 1/20 gradient) to give another portion of product. The total amount of desired product is 355 mg (82%).
  • Step 4 To a suspension of ieri-butyl 4-(2-(3-bromo-5-nitrophenyl)-5- oxo-5H-[l,3,4]thiadiazolo[3,2-a]pyrimidin-7-yl)piperazine- 1-carboxylate (460 mg, 0.86 mmol) in EtOH (5 ml) and water (1 ml) are added iron powder (239 mg, 4.38 mmol) and NH 4 CI (137 mg, 2.57 mmol) and the mixture is heated at 70 °C for 5 h. After cooling to room temperature, EtOAc (30 ml) is added and the mixture is further stirred for 10 min then filtered through a pad of Celite.
  • Step 5 To a solution of ieri-butyl 4-(2-(3-amino-5-bromophenyl)-5- oxo-5H-[l,3,4]thiadiazolo[3,2-a]pyrimidin-7-yl)piperazine- 1-carboxylate (30.0 mg, 0.059 mmol) in DMF (2 ml) are added Boc-Gly-OH (20.7 mg, 0.118 mmol), HATU (45.0 mg, 0.118 mmol) and i_ Pr 2 NEt (31 ⁇ , 0.177 mmol). The mixture is stirred at room temperature for 2 h. EtOAc (10 ml) is added and the solution is washed with H 2 0 and brine.
  • Step 6 To a solution of tert-butyl 4-(2-(3-bromo-5-(2-(1 ⁇ 2rt- butoxycarbonylamino)-acetamido)phenyl)-5-oxo-5H-[l,3,4]thiadiazolo[3,2- a]pyrimidin-7-yl)piperazine-l-carboxylate (30 mg, 0.045 mmol) in DCM (2 ml) is added TFA (0.5 ml) and the mixture is stirred for 1 h.
  • Example 2 Using the procedures described or similarly described in Example 1, the compound of Example 2 is prepared except that 2-methyl-3-nitrobenzoic acid is used as starting material in step 1. ] H NMR (400 MHz, DMSO- ) ⁇ 10.18 (s, IH), 9.20-9.00 (br.s., 2H), 8.35-8.10 (br.
  • Example 3 Using the procedures described or similarly described in Example 1, the compound of Example 3 is prepared except that 3-trifluoromethyl-5-nitrobenzoic acid is used as starting material in step 1. ]
  • Example 4 Using the procedures described or similarly described in Example 1, the compound of Example 4 is prepared except 2-bromo-3-nitrobenzoic acid is used as starting material in step 1. The peaks of some protons split into two groups with integration ratio of major/minor 1.7/1.
  • Examples 5-8 The compounds of Examples 5-8 are prepared as described or similarly described in the procedures below:
  • tert-butyl 4-(2-(3-amino-2-vinylphenyl)-5-oxo-5H-[l,3,4]thiadiazolo- [3,2-a]pyrimidin-7-yl)piperazine-l-carboxylate is carried on as described in steps 5 and 6 of Example 1 to yield 2-amino-N-(3-(5-oxo-7-(piperazin-l-yl)-5H- [l,3,4]thiadiazolo[3,2-a]pyrimidin-2-yl)-2-vinylphenyl)acetamide.
  • the compound of this example is prepared using the procedure as similarly described in Example 5 except the vinyl group on tert-butyl 4-(2-(3-(2-((tert- butoxycarbonyl)amino)acetamido)-2-vinylphenyl)-5-oxo-5H-[l,3,4]thiadiazolo[3,2- a]pyrimidin-7-yl)piperazine-l-carboxylate is subjected to hydrogenation by carrying out the reaction under usual condition with Pd/C under 1 atm H 2 . After removing the catalyst, the crude product is directly used for the next step, deprotection of -Boc groups, without further purification.
  • Example 7 The compound of Example 7 is prepared using similar procedure as described in Example 5 except tert-butyl 4-(2-(3-amino-5-bromophenyl)-5-oxo-5H- [l,3,4]thiadiazolo[3,2-a]pyrimidin-7-yl)piperazine-l-carboxylate is used as the starting material.
  • Example 8 The compound of Example 8 is prepared using similar procedure as described in Example 6 except tert-butyl 4-(2-(3-amino-5-bromophenyl)-5-oxo-5H- [l,3,4]thiadiazolo[3,2-a]pyrimidin-7-yl)piperazine-l-carboxylate is used as the starting material.
  • Example 9 Using the procedures described or similarly described in Example 1, the compound of Example 9 is prepared except 3-methyl-5-nitrobenzoic acid is used as starting material in step 1. ]
  • Example 10 The compound of Example 10 is prepared as described
  • Examples 11-12 The compounds of Examples 11-12 are prepared as described or similarly described in the procedures below:
  • Step 1 To a solution of ieri-butyl 4-(2-(3-amino-5-bromophenyl)-5- oxo-5H-[l,3,4]thiadiazolo[3,2-a]pyrimidin-7-yl)piperazine-l-carboxylate, (400 mg, 0.79 mmol), which may be prepared using similar procedures as described in this application, in 1,4-dioxane (7.2 ml) and water (2.4 ml) is added isopropenyl boronic acid pinacol ester (265 mg, 1.577 mmol), Pd(PPh 3 ) 4 (91 mg, 0.079 mmol) and potassium carbonate (218 mg, 1.577 mmol).
  • Step 2 To a solution of ieri-butyl 4-(2-(3-amino-5-(prop-l-en-2- yl)phenyl)-5-oxo-5H-[l,3,4]thiadiazolo[3,2-a]pyrimidin-7-yl)piperazine-l- carboxylate (375 mg, 0.80 mmol) in DMF (8 ml) is added Boc-Gly-OH (280 mg, 1.60 mmol), HATU (609 mg, 1.60 mmol) and i-Pr 2 NEt (0.42 ml, 2.40 mmol). The mixture is stirred at room temperature for 2 h.
  • Step 3 To a solution of teri-butyl 4-(2-(3-(2-((1 ⁇ 2ri- butoxycarbonyl)amino)acetamido)-5-(prop-l-en-2-yl)phenyl)-5-oxo-5H- [l,3,4]thiadiazolo[3,2-a]pyrimidin-7-yl)piperazine-l-carboxylate (50 mg, 0.80 mmol) in DCM (4 ml) is added TFA (1 ml) and the mixture is stirred for 1 h. After the removal of solvent in vacuo, the crude residue is directly purified by preparative HPLC to give the desired product (Example 11).
  • Step 4 To a solution of ieri-butyl 4-(2-(3-bromo-5-(2-(tert- butoxycarbonylamino)-acetamido)phenyl)-5-oxo-5H-[l,3,4]thiadiazolo[3,2- a]pyrimidin-7-yl)piperazine-l-carboxylate (120 mg, 0.19 mmol) in MeOH (20 ml) is added Pd/C (100 mg, 10wt% Pd). The hydrogenation is carried out under 1 atm hydrogen atmosphere overnight. After removing the catalyst and solvent, the crude product is directly used for the next step deprotection of -Boc (1/4 of TFA/DCM, v/v) and preparative HPLC purification to give the desired product (Example 12).
  • Examples 13-14 The compounds of Examples 13-14 are prepared as described or similarly described in the procedures below:
  • the compound of this example is prepared as described in Example 13 above except that the acetyl group of tert-butyl 4-(2-(3-acetyl-5-(2-((tert- butoxycarbonyl)amino)-acetamido)phenyl)-5-oxo-5H-[l,3,4]thiadiazolo[3,2- a]pyrimidin-7-yl)piperazine- 1 -carboxylate is further reduced to tert-butyl 4-(2-(3-(2- ((tert-butoxycarbonyl)amino)acetamido)-5-(l-hydroxyethyl)phenyl)-5-oxo-5H- [l,3,4]thiadiazolo[3,2-a]pyrimidin-7-yl)piperazine-l-carboxylate using sodium borohydride.
  • the compound of this example may be prepared according to the procedure described or similarly described in Example 14.
  • Examples 14-B and 14-C The compounds of Examples 14-B and 14-C are prepared as described or similarly described in the procedures below:
  • Step 1 To a suspension of thiosemicarbazide (0.52 g, 5.68 mmol) in pyridine (3 ml) cooled with ice/water is added 2-chloroisonicotinoyl chloride (1.00 g, 5.68 mmol) dropwise. The addition is completed in 20 min. Then the mixture is allowed to warm to room temperature and stirred for 4 h. The mixture is poured into ice/water and the solid starts to precipitate. The solid is filtered and washed with minimum amount of EtOAc to remove impurities to give the desired product as a white solid (0.60 g, 46%).
  • Step 2 Polyphosphoric acid (PPA) (20 ml) is preheated at 100 °C. To this hot PPA is added 2-(2-chloroisonicotinoyl)hydrazinecarbothioamide (3.50 g, 15.17 mmol) portionwise. After the addition, the mixture is further stirred at this temperature for 1 h. After cooling to room temperature, the mixture is slowly poured into ice and the pH is adjusted to 9.0 with addition of ammonium hydroxide solution (37wt% in water). The solid precipitates out and is filtered, washed with EtOAc (3X50 ml). The EtOAc is combined and washed with brine, dried over sodium sulfate. After the removal of most EtOAc, the solid is filtered which is combined with the solid obtained in the first filtration to give a light yellow solid (2.80 g, 87%).
  • PPA Polyphosphoric acid
  • Step 3 To a solution 5-(2-chloropyridin-4-yl)-l,3,4-thiadiazol-2-amine (0.500 g, 2.35 mmol) in CH 3 CN (13 ml) is added methyl 3-chloro-3-oxopropanoate
  • Step 4 To a mixture of 7-chloro-2-(2-chloropyridin-4-yl)-5H- [l,3,4]thiadiazolo[3,2-a]pyrimidin-5-one (300 mg, 1.17 mmol) and tert-butyl piperazine-l-carboxylate (240 mg, 1.29 mmol) in CH 3 CN (12 ml) is added Hunig's base (0.245 ml, 1.40 mmol) and the mixture is microwaved at 100 °C for 2 h. After cooling to room temperature, solid starts to precipitate out. The solid is filtered and washed with EtOAc and collected.
  • Step 5 To a solution of tert-butyl 4-(2-(2-chloropyridin-4-yl)-5-oxo- 5H-[l,3,4]thiadiazolo[3,2-a]pyrimidin-7-yl)piperazine-l-carboxylate (160 mg, 0.36 mmol) in THF (5 ml) are added Boc-gly-NH 2 (124 mg, 0.72 mmol), XantPhos (124 mg, 0.14 mmol), Pd(OAc) 2 (24 mg, 0.07 mmol) and K 2 C0 3 (197 mg, 1.44 mmol). The microwave tube is purged with nitrogen for 1 min then sealed. The mixture is microwaved at 90 °C for 2 h.
  • Step 6 To a solution of tert-butyl 4-(2-(2-(2-((1 ⁇ 2ri- butoxycarbonyl)amino)acetamido)pyridin-4-yl)-5-oxo-5H-[l,3,4]thiadiazolo[3,2- a]pyrimidin-7-yl)piperazine-l-carboxylate (50 mg, 0.085 mmol) in DCM (1 ml) is added TFA (0.25 ml) and the mixture is stirred at room temperature for 2 h.
  • Step 1 5-nitronicotinic acid (500 mg, 2.97 mmol) is mixed with thionyl chloride (15 ml, 206 mmol) and the mixture is heated at 80 °C for 3.5 h. After the removal of thionyl chloride, the residue is dissolved in pyridine (2 ml) and thiosemicarbazide (271 mg, 2.97 mmol) is added. The mixture is stirred overnight at room temperature. The mixture is poured into ice and the precipitate is filtered and washed with EtOAc to give the desired product as a gray solid (110 mg, 15%).
  • Step 2 PPA (2 ml) is preheated to 100 °C and the 2-(5- nitronicotinoyl)hydrazinecarbothioamide (110 mg, 0.46 mmol) is added portionwise. The mixture is heated at this temperature for 1 h. After cooling to room temperature, the mixture is slowly poured into ice and the pH is adjusted to 9.0 with the addition of ammonium hydroxide solution (37wt in water). The solid precipitates out and is filtered and washed with EtOAc (3X5 ml). The EtOAc is combined, washed with brine and dried over sodium sulfate. After the removal of most EtOAc, the solid is filtered which is combined with the solid obtained in the first filtration to give a light yellow solid (100 mg, 98%).
  • Step 3 Step 3: To a solution 5-(5-nitropyridin-3-yl)-l,3,4-thiadiazol-2- amine (80 mg g, 0.36 mmol) in CH 3 CN (3.4 ml) is added methyl 3-chloro-3- oxopropanoate (0.054 ml, 0.50 mmol). The mixture is microwaved at 100°C for 12 min. After cooling to room temperature, POCI 3 (1.34 ml, 14.34 mmol) and Hunig's base (0.063 ml, 0.36 mmol) are added and the mixture is microwaved at 150°C for 30 min.
  • POCI 3 (1.34 ml, 14.34 mmol
  • Hunig's base 0.063 ml, 0.36 mmol
  • Step 4 To a mixture of 7-chloro-2-(2-chloropyridin-4-yl)-5H- [l,3,4]thiadiazolo[3,2-a]pyrimidin-5-one (30 mg, 0.097 mmol) and ieri-butyl piperazine-l-carboxylate (22 mg, 0.12 mmol) in CH 3 CN (2 ml) is added Hunig's (0.024 ml, 0.140 mmol) and the mixture is microwaved at 100 °C for 1 h. After cooling to room temperature, solid starts to precipitate out. The solid is filtered, washed with EtOAc and collected. The filtrate is concentrated in vacuo and the crude residue is purified by Biotage column chromatography (MeOH/DCM: 1/100 to 1/10 gradient) to give another portion of product. The total amount of desired product is 40 mg (yield: 90%).
  • Step 5 To a solution of ieri-butyl 4-(2-(5-nitropyridin-3-yl)-5-oxo-5H- [l,3,4]thiadiazolo[3,2-a]pyrimidin-7-yl)piperazine-l-carboxylate (40 mg, 0.087 mmol) in MeOH (3 ml) is added Raney-nickel in water slurry. Then hydrazine (0.027 ml, 0.87 mmol) is added dropwise. After the completion of addition, the mixture is stirred for another 5 min, then filtered through a pad of Celite to remove the catalyst. The filtrate is concentrated in vacuo and dried under vacuo to give the desired product (20 mg, 54%).
  • Step 6 To a solution of ieri-butyl 4-(2-(5-aminopyridin-3-yl)-5-oxo- 5H-[l,3,4]thiadiazolo[3,2-a]pyrimidin-7-yl)piperazine-l-carboxylate (20 mg, 0.047 mmol) in DMF (1 ml) is added Boc-gly-OH (16 mg, 0.093 mmol), HATU (35 mg, 0.093 mmol) and Hunig' s base (0.024 mmol, 0.14 mmol) and the mixture is stirred at room temperature for 3 h. EtOAc (10 ml) is added and the solution is washed with H 2 0 and brine. The organic layer is dried over Na 2 S0 4 . After removing EtOAc in vacuo, the residue is purified by Biotage column chromatography (MeOH/DCM: 1/100 to 1/10 gradient) to give the desired product (20 mg, 73%).
  • Step 7 To a solution of ieri-butyl 4-(2-(5-(2-(1 ⁇ 2ri- butoxycarbonylamino)acetamido)pyridin-3-yl)-5-oxo-5H-[l,3,4]thiadiazolo[3,2- a]pyrimidin-7-yl)piperazine-l-carboxylate (20 mg, 0.034 mmol) in DCM (2 ml) is added TFA (0.5 ml).
  • Example 14-F [0111] The compound of Formula P-II, wherein A is nitrogen, R 2 is fluoro
  • the starting material may be prepared by using the procedures described or similarly described above.
  • Example 15 Platelet adhesion and/or aggregation
  • the platelet adhesion assay may be conducted by a modification of the assay as described in Blue et al., Blood 2008, 111, 1248, the contents of which are incorporated by reference in their entirety. Thirty microliters of human fibrinogen (50 ⁇ g/mL) in Tris/saline (100 mM NaCl, 50 mM Tris/HCl, pH 7.4; American Diagnostica, Stamford, CT) may be added to black, clear-bottom, untreated polystyrene, nonsterile 384-well microtiter plate wells (Corning no. 3711; Acton, MA).
  • HBMT 138 mM NaCl, 12 mM NaHC0 3 , 10 mM HEPES, 2.7 mM KC1, 0.4 mM NaH 2 P0 4 , 0.1% glucose, 0.35% BSA, pH 7.4
  • An additional wash may be performed using HBMT with 1 mM MgCl 2 and 2 mM CaCl 2 .
  • Calcein-labeled platelets (final concentration 1 x 10 n /L) may be treated with Compounds of the Invention (final concentration of 100 ⁇ , 30 ⁇ , 10 ⁇ or 1 ⁇ ) at 22°C for 20 minutes. Thirty microliters of platelets may then be added to the wells. After 1 hour of adhesion, wells may be washed 3 times with HBMT-1 mM MgCl 2 /2 mM CaCl 2 and the plates may be read by a fluorescent microtiter plate reader (Envision;Perkin Elmer) to detect calcein fluorescence (490 nm excitation and 515 nm emission).
  • Negative controls consist of wells containing platelets without compounds of the invention. Positive controls are wells containing platelets and known inhibitors of ⁇ 3 ⁇ 4 ⁇ 3, including mAbs 7E3 and 10E5, and EDTA.
  • the platelet aggregation assay may be conducted by modification of the assay as disclosed in Blue et al., Blood 2008, 111, 1248, the contents of which are incorporated by reference in their entirety.
  • Citrated platelet-rich plasma PRP
  • PRP Citrated platelet-rich plasma
  • Compounds of the Invention final concentration of 100 ⁇ , 30 ⁇ , 10 ⁇ , 1 ⁇ , 0.30 ⁇ , ⁇ . ⁇ , 0.03 ⁇ and ⁇ . ⁇
  • ADP (5 - 20 ⁇ ) may be added to induce aggregation and the light transmittance is measured for 8 minutes.
  • the initial slopes of aggregation in the presence of different concentrations of the Compound tested may be used to generate an IC 50 .
  • the platelet adhesion and/or aggregation studies of various Compounds of the Invention will exhibit an IC 50 value of less than 100 ⁇ in a platelet aggregation study and/or inhibition of greater than 20% , preferably, greater than 30% at a concentration of 100 ⁇ in a platelet adhesion study.
  • the compound of Examples 14-B and 14-C inhibit platelet aggregation with an IC 50 of 53.6 + 15.5nM and 62.0 + ⁇ . ⁇ , respectively.

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Abstract

Cette invention concerne des composés et des compositions utilisés pour inhiber et/ou réduire le dépôt des plaquettes, leur adhésion et/ou leur agrégation. L'invention concerne par ailleurs une endoprothèse à élution médicamenteuse comprenant lesdits composés, et des méthodes pour le traitement ou la prophylaxie de troubles thrombotiques, notamment l'accident vasculaire cérébral, l'infarctus du myocarde, l'angor instable, les artériopathies périphériques, l'occlusion brutale après angioplastie ou mise en place d'une endoprothèse, et la thrombose après chirurgie vasculaire.
PCT/US2013/021749 2012-01-16 2013-01-16 Composés organiques WO2013109632A2 (fr)

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US14/372,488 US9303044B2 (en) 2012-01-16 2013-01-16 7-(piperazin-1-yl)-5H-[1,3,4]thiadiazolo[3,2-A]pyrimidin-5-ones for the treatment of thrombotic disorders
DK13738252.9T DK2804610T3 (en) 2012-01-16 2013-01-16 ORGANIC COMPOUNDS
ES13738252T ES2708201T3 (es) 2012-01-16 2013-01-16 Compuestos orgánicos
CN201380010564.7A CN104936598B (zh) 2012-01-16 2013-01-16 化合物、药物组合物及其用途
CA2861350A CA2861350C (fr) 2012-01-16 2013-01-16 Derives de thiadiazolo-pyrimidin-5-one comme antagonistes aiib-beta-3
EP13738252.9A EP2804610B1 (fr) 2012-01-16 2013-01-16 Composés organiques
IN6580DEN2014 IN2014DN06580A (fr) 2012-01-16 2013-01-16
AU2013209884A AU2013209884C1 (en) 2012-01-16 2013-01-16 Organic compounds

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9073945B2 (en) 2006-11-08 2015-07-07 The Rockefeller University Alpha-IIb-beta-3 inhibitors and uses thereof
WO2023064879A1 (fr) * 2021-10-13 2023-04-20 Remix Therapeutics Inc. Composés et procédés de modulation de l'épissage d'acides nucléiques

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU2011279008B2 (en) * 2010-07-16 2016-06-23 Icahn School Of Medicine At Mount Sinai Organic compounds
CA3103965A1 (fr) * 2018-06-19 2019-12-26 Celecor Therapeutics, Inc. Ruc-4 deutere
BR112023016440A2 (pt) * 2021-02-17 2023-10-10 Celecor Therapeutics Inc Formulações de ruc-4 estáveis
KR20230157354A (ko) * 2021-02-17 2023-11-16 셀레코어 테라퓨틱스, 인크. 치료 방법

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009024615A1 (fr) 2007-08-23 2009-02-26 Novartis Ag Sulfones cycliques substituées par amino-benzyle, utiles en tant qu'inhibiteurs de bace
US20100150913A1 (en) 2006-11-08 2010-06-17 The Rockefeller University Organic compounds

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2823686A1 (de) * 1978-05-31 1979-12-06 Bayer Ag Imidazo eckige klammer auf 2.1-b eckige klammer zu eckige klammer auf 1.3.4 eckige klammer zu -thiadiazole
US4548938A (en) * 1981-07-15 1985-10-22 Janssen Pharmaceutica N.V. 5-H-1,3,4-thiadiazolo[3,2-a]pyrimidin-5-one compounds
AU2011279008B2 (en) * 2010-07-16 2016-06-23 Icahn School Of Medicine At Mount Sinai Organic compounds

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20100150913A1 (en) 2006-11-08 2010-06-17 The Rockefeller University Organic compounds
US8173661B2 (en) 2006-11-08 2012-05-08 The Rockefeller University Alpha-IIB-beta-3 inhibitors and uses thereof
WO2009024615A1 (fr) 2007-08-23 2009-02-26 Novartis Ag Sulfones cycliques substituées par amino-benzyle, utiles en tant qu'inhibiteurs de bace

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
ANGEW. CHEM. INT. ED., vol. 50, 2011, pages 3497 - 3450
BLUE ET AL., BLOOD, vol. 111, 2008, pages 1248
MCCOY ET AL., PROBE REPORTS FROM THE NIH MOLECULAR LIBRARIES PROGRAM, 27 March 2010 (2010-03-27), pages 1 - 8
See also references of EP2804610A4

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9073945B2 (en) 2006-11-08 2015-07-07 The Rockefeller University Alpha-IIb-beta-3 inhibitors and uses thereof
WO2023064879A1 (fr) * 2021-10-13 2023-04-20 Remix Therapeutics Inc. Composés et procédés de modulation de l'épissage d'acides nucléiques

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EP2804610A4 (fr) 2016-04-20
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DK2804610T3 (en) 2019-02-25
EP2804610B1 (fr) 2018-10-31
CA2861350C (fr) 2020-12-15
CN104936598B (zh) 2017-11-03
AU2013209884A8 (en) 2014-08-14
US9303044B2 (en) 2016-04-05
US20150050325A1 (en) 2015-02-19
WO2013109632A3 (fr) 2015-06-18
AU2013209884C1 (en) 2018-01-18
AU2013209884A1 (en) 2014-08-07
EP2804610A2 (fr) 2014-11-26
CN104936598A (zh) 2015-09-23
ES2708201T3 (es) 2019-04-09

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